1. Field of the Invention
This invention relates to novel arylcycloalkanepolyalkylamines that are useful as anti-psychotic, anti-ischemia, anti-stroke, anti-dementia and anti-convulsant agents. In particular, this invention relates to arylcycloalkanepolyalkylamines that are selective high-affinity ligands to the sigma binding-sites and their preparation and use for treatment of psychoses, ischemia, stroke, dementia and convulsions. These selective, high affinity sigma ligands contain three basic chemical components: a) an arylcycloalkyl group, b) an amine group and c) an intermediate chain.
2. Related Disclosures
Psychoses are major mental disorders of organic and/or emotional origins characterized by derangement of the personality and loss of contact with reality. They are a serious problem facing society. People suffering from various psychotic states are often unable to exist on their own and require either institutionalization or home care and supervision, both of which are very costly to society.
Over the past 35 years, the development of various psychotropic drugs has produced major changes in the management of psychotic mental disorders. The use of these drugs has decreased the need for continuous or extended hospital care and allowed restoration of a patient's basic functioning to a level necessary for a satisfying and productive life.
The antipsychotic drugs include phenothiazines chlorpromazine, triflupromazine, mesoridazine, perphenazine, prochlorperazine and trifluoperazine; thioxanthenes chlorprothiaxine and thiothixine; dihydroindolone molindone; dibenzoxazepine loxapin; diphenylbutylpiperidine pimoside; and butyrophenones haloperidol and droperidol. Although these and other similar drugs are effective in the treatment of acute and chronic schizophrenia, depression, manic-depressive psychosis and other psychotic conditions, they are accompanied by a variety of undesirable and deleterious side effects. These side effects include drowsiness, sedation, hypotension, reduction of convulsive seizure threshold, ocular and skin pigmentation, photosensitization, hepatotoxicity, chronic cholestatic liver disease and cardiac arrhythmias. The extrapyramidal symptoms (EPS), such as akathisia, dystonia, tremors and rigidity, tardive dyskinesia, parkinsonism, etc., however, represent the most serious side-effect liability of the antipsychotic drugs. Because of the severity of such side effects, many patients avoid or refuse to use antipsychotic drugs and, when untreated, revert to their original psychotic conditions.
Thus, it would be extremely valuable to have available antipsychotic agents that are free of this undesirable side effect liability, especially that caused by EPS.
Receptors are specific, chemically defined sites on the surface of cells and are frequently classified according to their ability to bind certain ligands (compounds). When bound to a receptor, these ligands can act directly by stimulating or inhibiting normal receptor function, or indirectly by blocking the binding site and preventing normal (endogenous) ligand-binding. Many pharmacologically active agents act at the receptor level by either mimicking the action of an endogenous ligand (agonist) or by blocking the action of an endogenous ligand (antagonist).
Neurotransmitters are endogenous ligands that chemically affect the receptors on nerve cells or the organs innervated by these cells. Under normal physiological conditions, a certain level of neurotransmitter is released and/or present in the vicinity of its specific receptors. When the normal level of a neurotransmitter is disturbed, pathological conditions such as the various forms of psychoses, depression, schizophrenia, Parkinson's disease, Huntington's chorea, Grave's or Cushing's disease, etc., may develop.
Most known receptors have a developed pharmacology of agents that act as agonists or antagonists. For example, antagonists are known that block the actions of the neurotransmitters dopamine, adrenalin, noradrenalin and acetylcholine. Many neurotransmitter agonists and antagonists have been identified and are described in the neuroscientific literature.
Despite extensive pharmacological research and the continuing development of progressively more sophisticated laboratory techniques, many receptor systems and/or their biological effects remain unknown. The availability of selective high-affinity ligands greatly facilitates the determination of a particular receptor's biological role. Such ligands can also be useful for treating pathological conditions arising from the dysfunction of their target receptor system. Thus, new compounds that can specifically affect the function of known receptor systems are always in demand.
The principal antipsychotic neuroleptic drugs currently clinically employed act as dopamine D-2 receptor antagonists. This receptor antagonism is believed to mediate the therapeutic antipsychotic actions as well as the serious EPS side-effects of the neuroleptics. Drugs with high affinities for the D-2 subclass of postsynaptic dopamine receptors are known to attenuate the positive symptoms (e.g., hallucinations, delusions, and formal thought disorder) of schizophrenia. Such activity has led to the hypothesis that schizophrenia is a consequence of hyperdopaminergic transmission [FASEB, 3:1869 (1989)].
Since known neuroleptic drugs are only palliative and are accompanied by prevalent, serious side effects, a significant effort has been directed toward the development of new antipsychotic drugs that might act in a novel fashion. Recent discoveries suggest that other, non-dopaminergic mechanisms also play a role in the development of schizophrenic pathology and other psychoses. For example, the .alpha.-adrenoceptor, .beta.-adrenoceptor, serotonin (5-HT), muscarinic acetylcholine, and lately phencyclidine (PCP) and sigma (.sigma.) receptors have been implicated in various psychotic symptoms. The existence of alternate mechanisms makes possible the development of new intervention strategies for treatment of schizophrenia with reduced EPS liability.
Animal behavioral paradigms, predictive of antipsychotic efficacy, identified a number of candidates that may lack the side effects associated with typical neuroleptic therapy [Eur. J. Pharmacol., 155:345 (1988)]. When evaluated at dopamine D-2, 5-HT, .alpha.- and .beta.-adrenoceptor, muscarine acetylcholine, PCP and sigma receptors, these compounds had a sole common feature; high affinity for .sigma. receptors. Two of these drugs, rimcazole and remoxipride, which were shown in clinical trials to display clinical antipsychotic effects, are both potent and selective .sigma. receptor ligands. Based on these findings, it has been suggested that inhibitors of .sigma. receptors may act as antipsychotic agents.
The role of sigma receptors in mediating psychoses has been investigated for compounds that share an affinity for this receptor including the benzomorphans such as n-ally-normetazocine and cyclazocine, PCP, and antipsychotic drugs like haloperidol. The clinically effective neuroleptic haloperidol is a potent dopamine D-2 receptor antagonist, but at the same time possesses a high affinity for the .sigma. site [Neurology, 38:961 (1988)].
PCP (1-(1-phenylcylohexyl)piperidine) is a psychomimetic drug with diverse biochemical effects in the central nervous system (CNS) and potent behavioral responses. Specific PCP receptors have been described in the brain, having a pharmacological selectivity and potency corresponding to the behavioral effects of PCP. PCP is known to influence transmitter metabolism in several different CNS regions, to alter gross motor activity and spatial alternation performance and to induce stereotypic movements [Synapse, 1:497 (1987)]. In humans, PCP causes psychotic reactions such as hallucinations, thought disorders and paranoid delusions similar to an acute schizophrenic episode.
Sigma receptors were identified based on the actions of ((.+-.)-N-allylnormetazocine and related benzomorphan alkaloids. [J. Pharmacol. Exp. Ther., 197:517 (1976)]. They are distinguished on the basis of the following four characteristics: (a) stereoselectivity for dextrorotatory benzomorphans; (b) insensitivity to naloxone; (c) high affinity for haloperidol and (d) insensitivity to dopamine and apomorphine. Ligands that bind to .sigma. receptors are haloperidol (4-[4-(p-chlorophenyl)-4-hydroxypiperidino]-4'-fluorobutyrophenone); (+)-3-PPP ((+)-3-(3-hydroxyphenyl)-N-(1-propyl)piperidine), DTG (1,3-di-o-tolylguanidine); dextrallorphan; and benzomorphans such as N-allylnormetazocine (NAN), pentazocine (2-dimethylallyl-5,9-dimethyl-2-hydroxy-benzomorphan), and cyclazocine (3-(cyclopropylmethyl)-1,2,3,4,5,6-hexahydro-6,11-dimethyl-2,6-methano-3-b enzazocin-8-ol). Structures of several sigma receptor ligands are shown in FIG. 1.
Based on these observations, the conclusion was reached that .sigma. receptors are non-dopaminergic, non-opioid receptors that bind antipsychotic drugs as well as the (+) enantiomers of benzomorphans.
Two distinct populations of sigma receptors have been identified and labeled on .sigma..sub.p - and .sigma..sub.h -receptors. The haloperidol-sensitive .sigma..sub.h receptor sites exhibit a drug selectivity pattern and a brain distribution that differs from phencyclidine (PCP) - sensitive .sigma..sub.p receptors, dopamine receptors and all other known classes of receptors. Henceforth, the term ".sigma. receptor" will refer to the haloperidol-sensitive .sigma. receptor (.sigma..sub.h).
The .sigma. receptors are found in many brain areas involved in the control of movement. The observation that microinjections of DTG into the red nucleus and substantia nigra produce vigorous contralateral circling behavior, suggests that .sigma. binding sites represent biologically functional receptors that are active in the neural control of movement [Neurology, 38:961 (1988)].
One high-affinity, .sigma.-selective antipsychotic agent, rimcazole (cis-9-[3-(3,5-dimethyl-1-piperazinyl)propyl]carbozole), was shown to antagonize climbing behavior in mice without producing the cataleptic state typically associated with the induction of EPS side effects. Unlike classical neuroleptics, rimcazole did not influence conditioned avoidance responses in rat. Also unlike classical neuroleptics, rimcazole did not exert its action at the level of postsynaptic dopamine receptors in the mesolimbic area. However, rimcazole was able to competitively inhibit specific binding of the .sigma. receptor ligand NAN to specific membranes prepared from rat spinal cord and brain.
Previous attempts have been made to determine structural requirements for the interaction of PCP analogs with .sigma. receptors. PCP analogs with an increased distance between the phenyl and piperidine rings show an increased affinity for .sigma. receptors, at the expense of PCP receptor affinity [FASEB, 4:A359 (1990)].
From the literature cited above, it is clear that o receptor dysfunction may be a naturally occurring pathogenic mechanism of psychosis in humans. Consequently, selective high-affinity .sigma. receptor ligands may be valuable for treatment of psychotic symptoms such as delusions, hallucinations, depersonalization, dysphoria, affective liability, etc. They may also be effective against other conditions linked to .sigma. receptor function such as ischemia, stroke, dementia and cocaine-induced convulsions. These ligands would be highly selective for .sigma. receptors; they would not act on other receptors at antipsychotic doses, including PCP receptors; they would have potent antipsychotic therapeutic properties; and they would not produce undesirable side effects.
The current invention concerns a group of selective high affinity .sigma. receptor ligands that are effective as antipsychotics, antiischemics and anticonvulsants, which do not possess undesirable side-effects.